Social environment is associated with gene regulatory variation in the rhesus macaque immune system
Open accessAbstract
Variation in the social environment is a fundamental component of many vertebrate societies. In humans and other primates, adverse social environments often translate into lasting physiological costs. The biological mechanisms associated with these effects are therefore of great interest, both for understanding the evolutionary impacts of social behavior and in the context of human health. However, large gaps remain in our understanding of the mechanisms that mediate these effects at the molecular level. Here we addressed these questions by leveraging the power of an experimental system that consisted of 10 social groups of female macaques, in which each individual's social status (i.e., dominance rank) could be experimentally controlled. Using this paradigm, we show that dominance rank results in a widespread, yet plastic, imprint on gene regulation, such that peripheral blood mononuclear cell gene expression data alone predict social status with 80% accuracy. We investigated the mechanistic basis of these effects using cell type-specific gene expression profiling and glucocorticoid resistance assays, which together contributed to rank effects on gene expression levels for 694 (70%) of the 987 rank-related genes. We also explored the possible contribution of DNA methylation levels to these effects, and identified global associations between dominance rank and methylation profiles that suggest epigenetic flexibility in response to status-related behavioral cues. Together, these results illuminate the importance of the molecular response to social conditions, particularly in the immune system, and demonstrate a key role for gene regulation in linking the social environment to individual physiology.
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Those epigenetic profiles are only weakly correlated with differences in immune cell gene expression.
“However, those epigenetic profiles are only weakly correlated with differences in immune cell gene expression [7], [41], and much remains to be learned about what role epigenetic dynamics play in social genomic effects such as the CTRA.”
From Human Social Genomics (2014) · cites this paper as [7]
Environmental conditions clearly influence epigenetic profiles in human immune cells, and some studies have linked immune cell DNA methylation profiles to specific social environmental conditions such as low social status and early life stress exposure.
“Environmental conditions clearly influence epigenetic profiles in human immune cells [37], and some studies have begun to link immune cell DNA methylation profiles to specific social environmental conditions such as low social status [7] and early life stress exposure [38]–[41].”
From Human Social Genomics (2014) · cites this paper as [7]
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Cites
Cutadapt removes adapter sequences from high-throughput sequencing reads
Martin, M. (2011) · EMBnet.journal · doi:10.14806/ej.17.1.200 · Cited by 33,889 · see citing works
BEDTools: a flexible suite of utilities for comparing genomic features
Quinlan, A. R., & Hall, I. M. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq033 · Cited by 27,437 · see citing works
Observational study of behavior: sampling methods
Altmann, J. (1974) · Behaviour · doi:10.1163/156853974x00534 · Cited by 13,891 · see citing works
Statistical significance for genomewide studies
Storey, J. D., & Tibshirani, R. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1530509100 · Cited by 9,692 · see citing works
Social Relationships and Health
House, J. S., Landis, K. R., & Umberson, D. (1988) · Science · doi:10.1126/science.3399889 · Cited by 7,073 · see citing works
Advances in kernel methods: support vector learning
Schölkopf, B., Burges, C. J. C., & Smola, A. J. (1999) · doi:10.5555/299094 · Cited by 5,809 · see citing works
Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications
Krueger, F., & Andrews, S. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr167 · Cited by 5,161 · see citing works
Human DNA methylomes at base resolution show widespread epigenomic differences
Lister, R., Pelizzola, M., Dowen, R. H., Hawkins, R. D., Hon, G., Tonti-Filippini, J., Nery, J. R., Lee, L., Ye, Z., Ngo, Q.-M., et al. (2009) · Nature · doi:10.1038/nature08514 · Cited by 4,673 · see citing works
Making Large-Scale SVM Learning PracticalPreprint
Joachims, T. (1998) · RePEc: Research Papers in Economics · doi:10.17877/de290r-14262 · Cited by 4,514 · see citing works
Yu, J., Pressoir, G., Briggs, W. H., Bi, I. V., Yamasaki, M., Doebley, J., McMullen, M. D., Gaut, B. S., Nielsen, D. M., Holland, J. B., et al. (2005) · Nature Genetics · doi:10.1038/ng1702 · Cited by 4,155 · see citing works
The influence of social hierarchy on primate health
Sapolsky, R. M. (2005) · Science · doi:10.1126/science.1106477 · Cited by 2,113 · cited 2× · see citing works
“However, the current results support the idea that changes in gene regulation help to explain links between the social environment and physiology, potentially supplying an important piece to the puzzle of how social effects “get under the skin” (3, 31).”
BackgroundResultlumi : a pipeline for processing Illumina microarray
Du, P., Kibbe, W. A., & Lin, S. M. (2008) · Bioinformatics · doi:10.1093/bioinformatics/btn224 · Cited by 2,028 · see citing works
Training linear SVMs in linear time
Joachims, T. (2006) · ACM SIGKDD Conference on Knowledge Discovery and Data Mining (KDD) · doi:10.1145/1150402.1150429 · Cited by 1,932 · see citing works
Efficient Control of Population Structure in Model Organism Association Mapping
Kang, H. M., Zaitlen, N., Wade, C. M., Kirby, A. W., Heckerman, D. E., Daly, M. J., & Eskin, E. (2008) · Genetics · doi:10.1534/genetics.107.080101 · Cited by 1,848 · see citing works
Covalent Modification of DNA Regulates Memory Formation
Miller, C. A., & Sweatt, J. D. (2007) · Neuron · doi:10.1016/j.neuron.2007.02.022 · Cited by 1,180 · see citing works
Increased methylation variation in epigenetic domains across cancer types
Hansen, K. D., Timp, W., Bravo, H. C., Sabunciyan, S., Langmead, B., McDonald, O. G., Wen, B., Wu, H., Liu, Y., Diep, D. H., et al. (2011) · Nature Genetics · doi:10.1038/ng.865 · Cited by 1,053 · see citing works
Self-citationHealth psychology: what is an unhealthy environment and how does it get under the skin?
Taylor, S. E., Repetti, R. L., & Seeman, T. (1997) · Annual Review of Psychology · doi:10.1146/annurev.psych.48.1.411 · Cited by 936 · see citing works
Reciprocal regulation of the neural and innate immune systems
Irwin, M. R., & Cole, S. W. (2011) · Nature Reviews Immunology · doi:10.1038/nri3042 · Cited by 910 · cited 2× · see citing works
“For instance,NR3C1, the GC receptor gene, plays a key role in linking behavior, HPA axis-mediated stress responses, and gene expression (30).”
BackgroundResultMiller, G. E., Chen, E., Fok, A. K., Walker, H., Lim, A., Nicholls, E. F., Cole, S., & Kobor, M. S. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0902971106 · Cited by 822 · see citing works
Social dominance and stress hormones
Creel, S. (2001) · Trends in Ecology & Evolution · doi:10.1016/s0169-5347(01)02227-3 · Cited by 816 · see citing works
Social regulation of gene expression in human leukocytes
Cole, S. W., Hawkley, L. C., Arevalo, J. M., Sung, C. Y., Rose, R. M., & Cacioppo, J. T. (2007) · Genome Biology · doi:10.1186/gb-2007-8-9-r189 · Cited by 745 · cited 1× · see citing works
“The gene regulatory role of NR3C1 has previously been linked to other social environmental responses via transcription factor motif analysis (16, 17), and could be further investigated using chromatin immunoprecipitation approaches.”
BackgroundSocial status and health in humans and other animals
Sapolsky, R. M. (2004) · Annual Review of Anthropology · doi:10.1146/annurev.anthro.33.070203.144000 · Cited by 739 · see citing works
Abbott, D. H., Keverne, E. B., Bercovitch, F. B., Shively, C. A., Mendoza, S. P., Wendy Saltzman, A., Snowdon, C. T., Ziegler, T. E., Banjevic, M., Garland, T., et al. (2003) · Hormones and Behavior · doi:10.1016/s0018-506x(02)00037-5 · Cited by 726 · see citing works
Social dominance in monkeys: dopamine D2 receptors and cocaine self-administration
Morgan, D., Grant, K. A., Gage, H. D., Mach, R. H., Kaplan, J. R., Prioleau, O., Nader, S. H., Buchheimer, N., Ehrenkaufer, R. L., & Nader, M. A. (2002) · Nature Neuroscience · doi:10.1038/nn798 · Cited by 674 · see citing works
Neuronal activity modifies the DNA methylation landscape in the adult brain
Guo, J. U., Ma, D. K., Mo, H., Ball, M. P., Jang, M.-H., Bonaguidi, M. A., Balazer, J. A., Eaves, H. L., Xie, B., Ford, E., et al. (2011) · Nature Neuroscience · doi:10.1038/nn.2900 · Cited by 669 · see citing works
Thomas, P. D. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg115 · Cited by 660 · see citing works
Gene Expression Profiles in the Brain Predict Behavior in Individual Honey Bees
Whitfield, C. W., Cziko, A.-M., & Robinson, G. E. (2003) · Science · doi:10.1126/science.1086807 · Cited by 618 · see citing works
The Effect of In Vivo Hydrocortisone on Subpopulations of Human Lymphocytes
Fauci, A. S., & Dale, D. C. (1974) · Journal of Clinical Investigation · doi:10.1172/jci107544 · Cited by 607 · see citing works
The Influence of Dominance Rank on the Reproductive Success of Female Chimpanzees
Pusey, A. E., Williams, J. M., & Goodall, J. R. (1997) · Science · doi:10.1126/science.277.5327.828 · Cited by 593 · see citing works
Maximum-Likelihood Estimation of Relatedness
Milligan, B. G. (2003) · Genetics · doi:10.1093/genetics/163.3.1153 · Cited by 538 · see citing works
The social environment and the epigenome
Moshe Szyf, A., McGowan, P. O., & Meaney, M. J. (2007) · Environmental and Molecular Mutagenesis · doi:10.1002/em.20357 · Cited by 533 · see citing works
Dominance rank and mating success in male primates
Cowlishaw, G., & Dunbar, R. (1991) · Animal Behaviour · doi:10.1016/s0003-3472(05)80642-6 · Cited by 488 · see citing works
Status Syndrome: A Challenge to Medicine
Marmot, M. G. (2006) · JAMA · doi:10.1001/jama.295.11.1304 · Cited by 372 · see citing works
Life at the Top: Rank and Stress in Wild Male Baboons
Gesquiere, L. R., Learn, N. H., Simao, M. C., Onyango, P. O., Alberts, S. C., & Jeanne Altmann, A. (2011) · Science · doi:10.1126/science.1207120 · Cited by 343 · see citing works
Hypercortisolism associated with social subordinance or social isolation among wild baboons
Sapolsky, R. M. (1997) · Archives of General Psychiatry · doi:10.1001/archpsyc.1997.01830240097014 · Cited by 318 · see citing works
Rapid Behavioral and Genomic Responses to Social Opportunity
Burmeister, S. S., Jarvis, E. D., & Fernald, R. D. (2005) · PLoS Biology · doi:10.1371/journal.pbio.0030363 · Cited by 275 · see citing works
van Noordwijk, M. A., & van Schaik, C. P. (1999) · Primates · doi:10.1007/bf02557705 · Cited by 272 · see citing works
Newman, T. K., Syagailo, Y. V., Barr, C. S., Wendland, J. R., Champoux, M., Grässle, M., Suomi, S. J., Higley, J. D., & Lesch, K. (2004) · Biological Psychiatry · doi:10.1016/j.biopsych.2004.10.012 · Cited by 257 · see citing works
Cohen, S., Line, S. W., Manuck, S. B., Rabin, B. S., Heise, E. R., & Kaplan, J. R. (1997) · Psychosomatic Medicine · doi:10.1097/00006842-199705000-00001 · Cited by 233 · see citing works
Variability in reproductive success viewed from a life‐history perspective in baboons
Jeanne Altmann, A., & Alberts, S. C. (2003) · American Journal of Human Biology · doi:10.1002/ajhb.10157 · Cited by 228 · see citing works
Grozinger, C. M., Fan, Y., Hoover, S. E., et al. (2007) · Molecular Ecology · doi:10.1111/j.1365-294x.2007.03545.x · Cited by 226 · see citing works
Esterling, B. A., Kiecolt‐Glaser, J. K., Bodnar, J. C., & Glaser, R. (1994) · Health Psychology · doi:10.1037/0278-6133.13.4.291 · Cited by 220 · see citing works
Barr, C. S., Newman, T. K., Schwandt, M. L., Shannon, C., Dvoskin, R. L., Lindell, S. G., Taubman, J., Thompson, B., Champoux, M., Lesch, K., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0403763101 · Cited by 205 · see citing works
Multi-species microarrays reveal the effect of sequence divergence on gene expression profilesPreprint
Gilad, Y., Rifkin, S. A., Bertone, P., Gerstein, M., & White, K. P. (2005) · Genome Research · doi:10.1101/gr.3335705 · Cited by 170 · see citing works
Self-citationModulated Modularity Clustering as an Exploratory Tool for Functional Genomic Inference
Stone, E. A., & Ayroles, J. F. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000479 · Cited by 120 · see citing works
Genome-wide transcriptional profiling linked to social class in asthma
Chen, E., Miller, G. E., Walker, H. A., Arevalo, J. M., Sung, C. Y., & Cole, S. W. (2008) · Thorax · doi:10.1136/thx.2007.095091 · Cited by 118 · see citing works
Jarrell, H., Hoffman, J. B., Kaplan, J. R., Berga, S. L., Kinkead, B. L., & Wilson, M. E. (2007) · Physiology & Behavior · doi:10.1016/j.physbeh.2007.11.042 · Cited by 113 · see citing works
Self-citationCole, S. W., Mendoza, S. P., & Capitanio, J. P. (2009) · Psychosomatic Medicine · doi:10.1097/psy.0b013e3181aa95a9 · Cited by 74 · see citing works
(2003) · Nucleic Acids Research · doi:10.1093/nar/gkg290 · Cited by 74 · see citing works
Using DNA microarrays to study gene expression in closely related species
Oshlack, A., Chabot, A. E., Smyth, G. K., & Gilad, Y. (2007) · Bioinformatics · doi:10.1093/bioinformatics/btm111 · Cited by 65 · see citing works
Self-citationMichopoulos, V., Checchi, M., Sharpe, D. I., & Wilson, M. E. (2011) · Hormones and Behavior · doi:10.1016/j.yhbeh.2011.02.002 · Cited by 60 · see citing works
Self-citationPaiardini, M., Hoffman, J. B., Cervasi, B., Ortiz, A. M., Connor‐Stroud, F., Silvestri, G., & Wilson, M. E. (2008) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2008.10.006 · Cited by 40 · see citing works
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Braveman, P., & Gottlieb, L. (2014) · Public Health Reports® · doi:10.1177/00333549141291s206 · Cited by 3,861 · see citing works
Slavich, G. M., & Irwin, M. R. (2014) · Psychological Bulletin · doi:10.1037/a0035302 · Cited by 2,206 · see citing works
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Snyder-Mackler, N., Burger, J. R., Gaydosh, L., Belsky, D. W., Noppert, G. A., Campos, F. A., Bartolomucci, A., Yang, Y. C., Aiello, A. E., O’Rand, A., et al. (2020) · Science · doi:10.1126/science.aax9553 · Cited by 679 · see citing works
Self-citationPowell, N. D., Sloan, E. K., Bailey, M. T., Arevalo, J. M. G., Miller, G. E., Chen, E., Kobor, M. S., Reader, B. F., Sheridan, J. F., & Cole, S. W. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1310655110 · Cited by 588 · see citing works
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- Authors
- Tung, J., Barreiro, L. B., Johnson, Z. P., Hansen, K. D., Michopoulos, V., Toufexis, D., Michelini, K., Wilson, M. E., & Gilad, Y.
- Affiliations
- University of Chicago (US)
- Emory University (US)
- Johns Hopkins University (US)
- University of Vermont (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-04-09
- Volume
- 109
- Issue
- 17
- Pages
- 6490-6495
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3340061
- OpenAlex
- W2063135131
- Cited by
- 277
- References
- 52
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 6 · 2023: 20 · 2022: 16 · 2021: 16 · 2020: 16 · 2019: 18 · 2018: 22 · 2017: 21 · 2016: 32 · 2015: 24 · 2014: 28 · 2013: 28 · 2012: 13
- FWCI
- 12.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH 081816, R01MH081816)
- National Human Genome Research Institute (R01HG005220)
- National Institute of General Medical Sciences (R01GM084996, GM077959, R01GM077959)
- National Center for Research Resources (RR-00 165, P51RR000165)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 046501, R01HD046501)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Animal Behavior and Reproduction
- Social Sciences › Psychology › Social Psychology › Primate Behavior and Ecology
- Keywords
- social environment, gene expression regulation, rhesus monkeys, immune system, peripheral blood mononuclear cells, glucocorticoid resistance, DNA methylation, epigenetic plasticity, social status, cell type-specific gene expression
- MeSH terms
- Animals, Behavior, Animal, Female, Macaca mulatta, Social Behavior, Evolution, Molecular, DNA Methylation, Gene Expression Profiling, Gene Regulatory Networks
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